It is widely accepted that insulin resistacne characterizes maturity-onset diabetes, obesity and aging. The term "resistance" is vague, and perhaps accounts for the popular use of the term. One characteristic of this "resistance" is the "failure" of insulin to promote glucose incorporation into glycogen. This failure is associated with kinetic changes in glycogen synthase activity. I propose by phosphorylation-dephosphorylation reactions. The roles of specific protein kinases and phosphatases will be assessed by a combined biochemical and genetic approach. The methods to be used include labelling the synthase with 32P in intact cells, purification of the enzyme, cleavage of the 32 P-synthase into small peptides, resolving the peptides and determining their 32p content. Specific assays for the kinases and phosphatases involved will be developed. These methods will be applied to tissues from animal models of insulin resistance to determine if insulin still can promote dephosphorylation. I will determine if phosphorylation at other specific sites prevents insulin promoted dephosphorylations from activating the enzyme. Ultimately, application of such methods to human tissue may disclose if an alteration in the phosphorylation state of glycogen synthase is part of the biochemical basis of insulin "resistance" associated with maturity-onset diabetes and obestiy.